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Familial Hematurias:
Alport Syndrome and Thin Basement Membrane Nephropathy
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Between 30% and 50% of children with persistent
hematuria have an inherited disorder of glomerular basement membranes
(GBM). Accurate diagnosis of familial hematuria is crucial for predicting prognosis
and providing accurate reproductive counseling.
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Most children and adolescents with familial glomerular hematuria
have either Alport syndrome (AS) or thin basement membrane nephropathy
(TBMN). All patients with AS, and about 50% of those with
TBMN, have mutations in genes that code for type IV collagen proteins,
the major collagenous constituents of basement membranes. About
80% of AS patients have X-linked disease due to mutations
in COL4A5, the gene encoding the a5 chain of type IV collagen (a5[IV]).
Autosomal recessive AS accounts for about 15% of patients
and arises from mutations in both alleles of COL4A3 or COL4A4, which encode
the a3(IV) and a4(IV) chains, respectively. About 5% of
AS patients have autosomal dominant disease, due to heterozygous
COL4A3 or COL4A4 mutations. However, most people with heterozygous
mutations of COL4A3 or COL4A4 have TBMN, a nonprogressive form of familial
hematuria.
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Persistent microscopic hematuria is the hallmark of AS, occurring
in 100% of X-linked AS males, 95% of X-linked
AS females, and all patients with autosomal recessive AS. Episodic
gross hematuria is common. The onset of hematuria in X-linked AS
males occurs during infancy. Since only 10% to 15% of
children with X-linked AS have de novo mutations,
most children with X-linked AS have a parent with hematuria. However,
normal parental urinalyses do not exclude a diagnosis of X-linked
AS. Each parent of a child with autosomal recessive AS is a heterozygous carrier
of a mutation in COL4A3 or COL4A4. Since about 50% of these
carriers are symptomatic, hematuria may be found in both parents,
one parent, or neither parent.
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Microscopic hematuria is also the cardinal clinical finding in
children with TBMN, who may have episodic gross hematuria, often
in association with acute infection. TBMN is a dominant disorder,
so hematuria is frequently found in a parent.
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As TBMN is typically nonprogressive, a family history of kidney
failure in a child with hematuria suggests a diagnosis of AS. A
family history of deafness should also raise suspicion for AS. Sensorineural
deafness develops in 80% of X-linked AS males and most
patients with autosomal recessive AS. The onset of measurable hearing deficits
typically occurs in late childhood. The hearing defect is bilateral
and initially involves high-frequency wavelengths, gradually extending
into conversational speech wavelengths over time. About 40% of
X-linked AS males exhibit ocular anomalies, including maculopathy,
anterior lenticonus, posterior polymorphous dystrophy, and recurrent
corneal erosions. The maculopathy and anterior lenticonus also occur
in autosomal recessive AS patients. Because TBMN is a renal-limited
disorder, the presence of extrarenal abnormalities like deafness
or ocular lesions in someone with hematuria makes a diagnosis of
TBMN unlikely. The absence of such findings does not rule out AS,
especially in the young patient.
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Rarely, X-linked AS is associated with smooth muscle tumors (leiomyomata)
of the esophagus; the tracheobronchial tree; and, in females, the
external genitalia. The AS-diffuse leiomyomatosis complex is a contiguous
gene syndrome resulting from deletions involving the adjacent COL4A5 and
COL4A6 genes on the X chromosome.
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Kidney function is usually well preserved during the first decade
of life in X-linked AS males. Overt proteinuria frequently appears
during late childhood or early adolescence, followed by development
of hypertension and renal insufficiency. About 50% of X-linked
AS males reach end-stage renal disease (ESRD) by age 25 and 90% by age
40. The probability of ESRD in X-linked AS females is 15% by
age 45 and 30% by age 60. Subjects with autosomal recessive
AS follow a course similar to X-linked AS males. In contrast, the
great majority of people with TBMN maintain normal urine protein
excretion and kidney function throughout life.
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AS and TBMN may be indistinguishable by routine light microscopy
(LM), immunofluorescence (IF), and electron microscopy (EM) in children.
While X-linked AS males will eventually exhibit LM abnormalities,
females may have normal-appearing kidneys by LM, as do individuals
with TBMN. In children with familial hematuria, the presence of
mesangial proliferation or focal segmental glomerulosclerosis on LM
suggests a diagnosis of AS.
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By EM, individuals with TBMN display diffuse glomerular basement
membranes (GBM) thinning. Since GBM thinning is also the earliest abnormality
in AS patients, TBMN and AS may be indistinguishable by EM in young
children. While GBM thinning is a static abnormality in TBMN, in
AS the GBM undergoes progressive thickening associated with fragmentation
of the lamina densa into multiple lamellae. In X-linked AS males,
these changes typically first appear during childhood, and the extent
of GBM displaying these alterations increases with age. In X-linked
AS females, the extent of GBM thickening ranges from focal to diffuse,
and the impact of aging on GBM thickening is variable.
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Immunostaining of kidney biopsy specimens using monospecific
antibodies shows diagnostic abnormalities in expression of a3(IV),
a4(IV), and a5(IV) chains in most X-linked and autosomal recessive
AS patients. Abnormal expression of the a5(IV) chain in epidermal
basement membranes occurs frequently in patients with X-linked AS,
allowing diagnosis by skin biopsy. Type IV collagen expression is
normal in patients with TBMN. Molecular analysis of the COL4A5 gene for
diagnosis of X-linked Alport syndrome (XLAS) is commercially
available in the United States and Europe.
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Patients who receive a diagnosis of TBMN do not require treatment
but do need regular monitoring to identify the small number who
will develop proteinuria, hypertension, or renal insufficiency due
to superimposed focal segmental glomerulosclerosis and those who
have received an inaccurate diagnosis of TBMN. There is no proven
treatment for AS other than renal transplantation, although studies
in transgenic mice have suggested several possible approaches, including
angiotensin II antagonism and stem cell transplantation. Transplant
outcomes in AS are generally excellent, although a small percentage
of patients develop severe crescentic glomerulonephritis of the
allograft mediated by antibodies to type IV collagen a5 or a3 chains.1,2
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Pierson syndrome is a recessive disorder consisting of congenital
nephrotic syndrome associated with ocular abnormalities (buphthalmos,
microcoria, cataracts) and hypotonia. Pierson syndrome arises from
mutations in the LAMB2 gene, which encodes the laminin b2 chain.3